Mode of action of long-term low-dose macrolide therapy for chronic sinusitis in the light of neutrophil recruitment.

Chronic sinusitis is a common inflammatory upper respiratory tract disease. One of the prominent features of this disease is persistent purulent effusion containing numerous emigrated neutrophils in the paranasal sinuses. Recent advances in sinusitis research have revealed two positive feedback mechanisms that explain the chronic neutrophil accumulation in the sinus. First, interleukin (IL)-1beta secreted by monocytes, macrophages and fibroblasts upregulates the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial cells, and thereby induces the extravascular transmigration of neutrophils. The emigrated neutrophils then secrete IL-1beta, which amplifies the expression of E-selectin and ICAM-1, resulting in further neutrophil infiltration. Second, chemoattractants including IL-8 in the sinus effusion initiate neutrophil exudation. Emigrated neutrophils then secrete IL-8, which elicits further neutrophil accumulation in the sinus effusion. Long-term low-dose macrolide therapy was first introduced for the treatment of diffuse panbronchiolitis in the 1980's. In the 1990's it was also shown to be an effective treatment for chronic sinusitis. The inhibitory effect of macrolides on neutrophil infiltration in inflammatory sites has been well documented in these diseases. Several lines of evidence indicate that macrolides do not function simply as a bactericide. In vitro studies have demonstrated various effects of macrolides on immunocompetent cells, inflammatory cells and airway epithelial cells. It has been shown that macrolides inhibit the production of IL-8 and IL-1beta and the expression of ICAM-1, suggesting that macrolides block the aforementioned dual positive feedback system of neutrophil recruitment and thereby exert their clinical efficacy in the treatment of chronic sinusitis. The inhibitory effects of macrolides on multiple steps in the process of neutrophil recruitment are presumably mediated by the inhibition of transcription factors such as nuclear factor-kB and activator protein-1. Further investigation of the mode of action of macrolides at the molecular level would lead to the development of safer and more effective drugs for the treatment of chronic sinusitis. In addition, the possible risk of this therapy such as the occurrence of resistant strains have to be carefully surveyed hereafter.